CA2012126A1

CA2012126A1 - Pharmaceutical composition with a positively inotropic activity, containing a synergistically acting mixture consisting of a benzimidazole and a ss-blocker, the preparation and use thereof

Info

Publication number: CA2012126A1
Application number: CA002012126A
Authority: CA
Inventors: Annerose Mauz; Willi Diederen; Jacques Van Meel; Wolfgang Wienen; Volkhard Austel
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1989-03-16
Filing date: 1990-03-14
Publication date: 1990-09-16
Also published as: IL93747A0; NZ232955A; JPH02282328A; ZA901975B; HU901586D0; DE3908531A1; HU205854B; EP0387762A2; KR900013960A; AU627848B2; AU5139090A; HUT53519A; EP0387762A3

Abstract

ABSTRACT

BENZIMIDAZOLE COMPOSITIONS

A pharmaceutical composition with a positive inotropic activity, containing a benzimidazole of formula I

Description

20~212~

55-120.510 Benzimidazole compositions The present invention relates to benzimidazole compositions, in particular pharmaceutical compositions containing a benzimidazole and a ~-blocker.
EP-B-8391 describes, inter alia, 5-(5-methyl-3-oxo- ~
4,5-dihydro-2H-6-pyridazinyl)-benzimidazoles substituted -~0 in the 2-position by an alkyl, hydroxyphenyl or methoxyphenyl group, that is compounds of formula I

H
:~'' '.

(wherein R represents a Cls alkyl, hydroxyphenyl or methoxyphenyl group).
These compounds, their 3H-tautomers, optically active antipodes and physiologically acceptable acid addition salts thereof have valuable pharmacological properties, such as antiviral, interferon-inducing and anti-ulcerative activities, and, move particularly, a cardiovascular activity, specifically cardiotonic, hypotensive and/or antithrombotic activities.
The term "cardiovascular activity" indicates an ~ ~
activity affecting the heart and blood vessels, which in ~ -the present instance occurs via an antithrombotic and cardiotonic activity and an effect on blood pressure.
In the light of these pharmacological properties, 1. ':' . :. ' ' '. ., '.'.' . '.- ' ' . . ' ., ' ' 201212~

possessed by the compounds of EP-B-8391, their 3H-tautomers, optically active 3ntipodes and the physiologically acceptable acid addition salts thereof are suitable for treating chronic heart insufficiency or angina pectoris and/or for the prevention of arterial thromboembolism and arterial occlusive diseases, for the treatment of ulcers and for fighting viruses and viral diseases.
Their use as therapeutic agents in chronic heart insufficiency is therefore based on the cardiotonic activity and, in the case of arterial thromboembolism and diseases of occlusion, on the antithrombotic activity thereof, particularly the thrombocyte activity.
Furthermore, EP-A-330052, which is not a prior publication, describes the combination of a benzimidazole of formula I mentioned hereinbefore and a ~-blocker which has anti-ischaemic effects on the heart.
It is also known that ~-blockers have hitherto been used predominantly for treating ischaemic heart diseases in which the heart muscle is not yet diseased, but recent attempts have also been made to use ~-blockers in cases of chronic heart insufficiency in order to relieve the strain on the heart and improve its pumping action.
In certain clinical cases which involve a reduced contractile force of the heart, e.g. heart insufficiency caused by various factors (see The American Journal of Cardiology 55, 9A-14A (1985)), ~-blockers showed an undesirable negative inotropic effect both in animal experiments and also in clinical trials.
It has now been found that the benzimidazoles of formula I in conjunction with ~-blockers not only negate _ the negative inotropic effects of the latter but actually lead to an improvement in heart function under physical stress. This finding is surprising, for during physical stress there is a physiological increase in heart function via an increase in the activity of the svmpathetic nervous system. This increased activity of .. . .. . . ~ - . ~ . . , ~ . .
.; . . .. .

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2012~25 the sympathetic nervous system has no effect when ~-blockers are present. A positive inotropic substance may compensate for the negative inotropic activity of a ~-blocker under resting conditions. ~owever, it cannot be predicted that the reflex adjustment of heart function to physical stress during a ~-blockade will be restored by a positive inotropic substance.
The present invention thus relates to new pharmaceutical compositions with a synergistic activity.
Viewed from one aspect therefore the invention provides a pharmaceutical composition having a positive inotropic activity and comprising a benzimidazole of formula I (as de~ined above) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof together with a ~-blocker.
Viewed from a further aspect the invention provides a process for the preparation of a pharmaceutical composition having positive inotropic activity, said process comprising combining, e.g. by admixture or by incorporation unmixed into combined dosage units, a benzimidazole of formula I (as defined above) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof together with a ~-blocker.
Viewed from a still further aspect the invention also provides the use of a ben~imidazole of formula I
(as defined above) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof for the manufact~re of a pharmaceutical composition ;
having positive inotropic activity containing a benzimidazole of formula I (as defined above) or a 3H-tautomer, optical isomer or physiologically acceptable -~ said addition salt thereof together with a ~-blocker for use in the treatment of heart conditions.
Viewed from another aspect the invention provides a . -method of treatment of heart conditions in the human or - non-human animal body, said method comprising 2012~26 administering to said body a benzimidazole of formula I
(as defined above) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof and a ~-blocker in concentrations sufficient to achieve a positive inotropic effect.
The compositions of the invention preferably contain benzimidazoles of formula I wherein R represents a methyl, 2-pentyl, 4-methoxyphenyl or 4-hydroxyphenyl group, particularly preferred are a 4-methoxyphenyl or 4-hydroxyphenyl group, or a 3H-tautomer, optically active antipode or physiologically acceptable acid addition salt thereof.
Examples of ~-blockers which may be used for the preparation of the compositions of the invention include a~enolol, metoprolol, pindolol, penbutolol, propanolol, carazolol, alprenolol, bupranolol, bisoprolol, mepindolol, metipranolol, betaxolol, acebutolol, nadolol, sotalol, bunitrolol, timolol and oxprenolol.
Particularly preferred pharmaceutical combinations are those wherein the two active substances have similar half lives, especially preferably a combination consisting of 2-t4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole (Compound A) and a ~-blocker such as atenolol, betaxolol, metoprolol, timolol, nadolol or propanolol or a combination consisting of 2-t4-hydroxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole (Compound B) and a ~-blocker such as metoprolol or pindolol. The first of t~.ese combinations is particularly suitable for oral _, administration and the second is particularly suitable for intravenous use.
The single dose for adults is from 0.1 to 10.0 mg, preferably from 1.0 to 2.5 mg, once or twice a day, for a compound of formula I or isomer or salt thereof, in . ~ . . . : . : . . .
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20~212~

order to obtain the activity according to the invention.
In contrast, the single dose of the ~-blocker used according to the invention may vary substantially because of its varying potency. The single dosage will ~`
be, for example, 25 to 100 mg, preferably 50 mg per day in the case of atenolol, 50 to 150 mg, preferably 100 mg, in the case of metoprolol, 5 to 15 mg, preferably 5 to lo mg in the case of timolol, 25 to 80 mg, preferably 30 to 60 mg in the case of nadolol and lo 50 to 100 mg, preferably S0 mg in the case of propanolol, divided into one or two single doses.
The new combinations according to the invention consisting of a ~-blocker and a benzimidazole of formula I or isomer or salt thereof were investigated using the combination of Compound A and atenolol as an example:

Influence on reflex adap~tation of heart function to physical stress Dogs (mongrel, both sexes, body weight 22 to 32 kg) were premedicated with a combination of 0.~ ml/kg of ~ -Polamivet~ and 0.05 ml/kg of Combelen~. After endotracheal intubation the animals were respirated with a mixture of 1% halothane, 24% 2 and 75% N20. Under sterile conditions the thorax was opened up at the 5th intercostal space on the left and a Konigsberg pressure recorder was introduced into the left ventricle through a rod incision at the apex. The pressure recorder was fixed to measure the pressure in the left ventricle, the cable was led out and the thorax closed. After the operation the animals were given 2 months convalescence in which they were familiarised with a treadmill.

Test procedure:
By the use of a treadmill (speed of treadmill:
- 0-2-4-6-8 km/h) the dogs were subjected to increasing physical stress, each stress stage lasting 3 minutes.

- . , . . : - , . - . .

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An initial run was used to determine the control values whilst a second run was carried out following intravenous administration of the test substances.
Throughout the experiment the pressure in the left ventricle was measured, and the heart rate LV-dP/dtmaX
(the maximum rate of pressure change for the left ventricle a measurement of the contractile force of the heart) were recorded. The following Table sets forth the values found:

Substance ~osage LV~dP/dtm~x (mmHg/s) i.v. at rest under maximum mg/kg stress during experiment (8 km/h) Control --- 1.88 + 0.13 2.98 + 0.20 Compound A 0.3 3.40 + 0.18 4.77 + 0.18 Control --- 1.98 + 0.20 2.88 + 0.19 Atenolol 0.1 1.88 + 0.16 2.15 + 0.17 Control --- 1.95 + 0.15 3.28 + 0.21 Compound A/Atenolol 0.3/0.1 2.57 + 0.14 4.18 + 0.20 ~I .

The compounds used according to the invention are well tolerated. Thus, for example, Compounds A and B
have the following acute toxicities:
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2012~26 Substance LD50 i.v. mg/kg p.o. mg/kg - -Compound A72 (rat) 600 (mouse) Compound B>100 ~rat) 10 The toxicities of the ~-blockers used in the combinations according to the invention are known from the literature and are well tolerated in therapeutic doses.
The combinations used according to the invention are also well tolerated; thus, for example, at the doses used for the combinations of Compound A and atenolol no toxic side effects could be observed.
Eor pharmaceutical use the active substances mentioned above may be formulated with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
~0 The following non-limiting Examples are provided in order further to illustrate the present invention:
,_, 2~2126 Exam~le 1 Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 50.0 mq of atenolol Composition:

Compound A 1.00 mg 10 Atenolol 50.00 mg Lactose 47.00 mg Corn starch 70.00 mg Polyvinylpyrrolidone 8.00 mg Aerosil 3.00 mg 15 Magnesium stearate 1.00 mq 180.00 mg Compound A, atenolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 8 mm in diameter.

Example 2 Tablets containing 0.5 mg of 2-~4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 50.0 mg of atenolol ., , . . . . ~ , .

. . -, . , - -- : : - - . ~ --- . .

~'' . -: . : , , ~

~012125 Composition:

Compound A 0.50 mg 5 Atenolol 50.00 mg Lactose 47.50 mg Corn starch 70.00 mg Polyvinylpyrrolidone 8 00 mg Aerosil 3.00 mg 10 Magnesium stearate 1.00 mq 180.00 mg Compound A, atenolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 8mm in diameter.

Example 3 2~
Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 30.0 m~ of nadolol : ~' .
Composition:

Compound A 1.00 mg Nadolol 30.00 mg Lactose 67.00 mg 30 Corn starch 70.00 mg Polyvinylpyrrolidone8.00 mg ` ~ Aerosil 3.00 mg Magnesium stearate l.00 mq 180.00 mg Compound A, nadolol, lactose and the corn starch are mixed together, granulated with a solution of ~ ~
.: '' 2~1212~

polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 8 mm in diameter.

Example_4 Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 60.0 mq of nadolol Composition:

Compound A l.00 mg 15 Nadolol 60.00 mg Lactose 37.00 mg Corn starch 70.00 mg Polyvinylpyrrolidone8.00 mg Aerosil 3.00 mg 20 Magnesium stearate 1.00 mq 180.00 mg Compound A, nadolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 8 mm in diameter.

Example 5 Capsules containing l.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 50.0 m~ of propanolol retard 50.00 mg of propanolol and 1.00 mg of Compound A are dispersed in a melt ~90C) of l9.00 mg of carnauba wax and 110.00 mg of stearyl alcohol.

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The dispersion is sprayed in a suitable container.
The spray nozzle should be chosen so as to produce droplets 300 to 800 ~m in diameter. The droplets are moved in free fall counter to an air current cooled to about 5 to 8C so that the droplets solidify. The spray material thus obtained is mixed with 1 mg of magnesium stearate and packed into hard gelatin capsules, size 3.

Example 6 Capsules containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 100 0 mq of metoprolol retard 100 mg of metoprolol and 1.00 mg of Compound A-are dispersed in a melt (90C) of 20.00 mg of carnauba wax and 59.00 mg of stearyl alcohol.
The dispersion is sprayed in a suitable container.
The spray nozzle should be chosen so as to produce droplets 300 to 800 ~m in diameter. The droplets are moved in free fall counter to an air current cooled to about 5 to 8C so that the droplets solidify. The spray material thus obtained is mixed with 1 mg of magnesium stearate and packed into hard gelatin capsules, size 3.

30 Example 7 ~

- _" Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5- .
methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 10.0 mg of timolol --.: : : ~ : . . . .. ~ . . . . . . .

~0~2~5~

Composition:

Compound A l.00 mg Timolol 10.00 mg 5 Lactose 51.00 mg Corn starch 50.00 mg Polyvinylpyrrolidone 5.00 mg Aerosil 2.00 mg Magnesium stearate 1.00 mq 120.00 mg Compound A, timolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 7 mm in diameter.

Example 8 Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl~-benzimidazole and 10.0 mq of betaxolol Composition:
Compound A 1.00 mg Betaxolol lO.00 mg ~ :
Lactose 51.00 mg Corn starch 50.00 mg 30 Polyvinylpyrrolidone 5.00 mg Aerosil 2.00 mg -~ Magnesium stearate 1.00 mq . 120.00 mg Compound A, betaxolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed - . . ~ . . . .. . :

20~2126 with Aerosil and magnesium stearate and compressed to form tablets 7 mm in diameter.

Example 9 Tablets containing 1.0 mg 2-(4-methoxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 100.0 mg of metoprolol Composition:

Compound A 1.00 mg Metoprolol 100.00 mg 15 Lactose 27.00 mg Corn starch 80.00 mg Polyvinylpyrrolidone8.00 mg Aerosil 3.00 mg Magnesium stearate1.00 m~
220.00 mg Compound A, metoprolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 9 mm in diameter.

Example ~0 Tablets containing 1.0 mg of 2-(4-methoxyphenyl)-5-(5- -methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and 5.0 ma of timolol -, :: - ', , . ~ :
~, . ....... . - .. --: .: ~: : . :. . .: , : . . - :.
::: . . : . . , -2012~2g composition:

Compound A 1.00 mg Timolol 5.00 mg 5 Lactose 56.00 mg Corn starch 50.00 mg Polyvinylpyrrolidone5.00 mg Aerosil 2.00 mg Magnesium stearate l.00 mq 12~.00 mg Compound A, timolol, lactose and the corn starch are mixed together, granulated with a solution of polyvinylpyrrolidone in ethanol, dried, screened, mixed with Aerosil and magnesium stearate and compressed to form tablets 7 mm in diameter.

Example ll Ampoules containing 1.0 mg of 2-~4-hydroxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole-hydrochloride and 5 ma of metoprolol Composition:
Compound B 1.00 mg Metoprolol 5.00 mg Mannitol 100.00 mg lN HCl ad pH 2.7 about2.4 ~1 -30 Water for injections adj2.0 ml :
Compound B, metoprolol and mannitol are dissolved in water, adjusted to pH 2.7 with hydrochloric acid, sterile filtered and transferred into 2 ml ampoules.
Sterilisation is effected for 20 minutes at 120C.
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2~2126 Example 12 Ampoules containing 1.0 mg of 2-(4-hydroxyphenyl)-5-(5-methyl-3-oxo~4,5-dihydro-2H-6-pyridazinyl)-benzimidazole-hYdrochloride and 0.4 mq pindolol _ Composition:

Compound B 1.00 mg 10 Pindolol 0.40 mg Mannitol 100.00 mg lN HCl ad pH 2.7 about .2.2 ~l Water for injections ad 2.0 ml Preparation:
Compound B, pindolol and mannitol are dissolved in water, adjusted to pH 2.7 with hydrochloric acid, sterile filtered and transferred into 2 ml ampoules.
Sterilisation is effected for 20 minutes at 120C.

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Claims

1. A pharmaceutical composition having a positive inotropic effect comprising a benzimidazole of formula I

(I) (wherein R represents a C1-5 alkyl, hydroxyphenyl or methoxyphenyl group) or a 3H-tautomer, optical isomer or or physiologically acceptable acid addition salt thereof together with a .beta.-blocker.

2. A composition as claimed in claim 1 containing a compund of formula I wherein R represents a methyl, 2-pentyl, 4-methoxyphenyl or 4-hydroxyphenyl group, or an isomer or salt thereof.

3. A composition as claimed in claim 1 containing a compound of formula I wherein R represents a 4-methoxyphenyl group, or an isomer or salt thereof.

4. A composition as claimed in claim 1 containing a compound of formula I wherein R represents a 4-hydroxyphenyl group, or an isomer or salt thereof.

5. A composition as claimed in any one of claims 1 to 4 wherein said .beta.-blocker is selected from atenolol, metoprolol, pindolol, penbutolol, propanolol, carazolol, alprenolol, bupranolol, bisoprolol, mepindolol, metipranolol, betaxolol, acebutolol, nadolol, sotalol, bunitrolol, timolol and oxprenolol.

6. A composition as claimed in claim 3 wherein said .beta.-blocker is selected from atenolol, betaxolol, metoprolol, timolol, nadolol and propanolol.

7. A composition as claimed in claim 4 wherein said .beta.-blocker is selected from metoprolol and pindolol.

8. A composition as claimed in any of claims 1 to 7 in dosage unit form containing per dosage unit 0.1 to 10 mg of a compound of formula I, or isomer or salt thereof.

9. A composition as claimed in any of claims 1 to 7 in dosage unit form containing per dosage unit 1 to 2.5 mg of a compound of formula I, or isomer or salt thereof.

10. A composition as claimed in any one of claims 1 to 9 further comprising at least one pharmaceutical carrier or diluent.

11. A pharmaceutical composition substantially as herein disclosed in any one of the Examples.

12. A process for the preparation of a pharmaceutical composition having positive inotropic activity, said process comprising combining, e.g. by admixture or by incorporation unmixed into combined dosage units, a benzimidazole of formula I (as defined in claim 1) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof together with a .beta.-blocker.

13. The use of a benzimidazole of formula I (as defined in claim 1) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof for the manufacture of a pharmaceutical composition having positive inotropic activity containing a benzimidazole of formula I (as defined above) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof together with a .beta.-blocker for use in the treatment of heart conditions.

14. A method of treatment of heart conditions in the human or non-human animal body, said method comprising administering to said body a benzimidazole of formula I
(as defined in claim 1) or a 3H-tautomer, optical isomer or physiologically acceptable said addition salt thereof and a .beta.-blocker in concentrations sufficient to achieve a positive inotropic effect.

15. Each and every novel composition, method and use herein disclosed.